Download Retinal Gene Therapy Coming of Age

HUMAN GENE THERAPY 24:242–244 (March 2013)
ª Mary Ann Liebert, Inc.
DOI: 10.1089/hum.2013.050
Commentary
Retinal Gene Therapy Coming of Age
Connie L. Cepko1 and Luk H. Vandenberghe 2
A
bout 5 years ago, results were made public from three
independent early phase clinical gene therapy trials for
an inherited and early onset form of retinal blindness called
Leber congenital amaurosis due to RPE65 deficiency (LCA2)
(Bainbridge et al., 2008; Cideciyan et al., 2008; Hauswirth et al.,
2008; Maguire et al., 2008). These studies were arguably a first
for an in vivo gene therapy approach to convincingly deliver
both on safety and efficacy. Indeed, subjects suffering from a
progressive loss of vision due to this retinal dystrophy regained moderate yet significant improvements in light perception and more complex vision. The binary hallmark of the
pathology of LCA2, as well as of most other hereditary retinal
blindness, is a combined dysfunction and degeneration of
photoreceptor cells (Bramall et al., 2010; Hartong et al., 2006).
For these retinal dystrophies with autosomal recessive inheritance, the hope and anticipation was that supplementation of the wild-type cDNA of the disease gene would
ameliorate both the dysfunction, resulting in improved vision,
and the degeneration, leading to preservation of photoreceptors. In the first reports from the LCA2 trials, vision tests
were primarily used to evaluate efficacy. However, a recently
published follow-up study by Cideciyan et al. (2013) studied
both aspects of the disease in subjects enrolled in one of the
three clinical trials. Remarkably, the authors found that while
gene therapy indeed leads to a long-term improvement of
vision, the photoreceptor cell layer continued to decline and
gene augmentation effectively leaves the degenerative processes undisturbed.
Cideciyan and others (2013) first performed a thorough
study of the natural history of the disease, which provided
essential data for interpreting the findings from the treated
patients. They used a key measure of retinal degeneration,
the thickness of the photoreceptor layer, referred to as the
outer nuclear layer (ONL). Improvements in imaging technology over the last decade now make it possible to noninvasively monitor ONL thickness by optical coherence
tomography (OCT), which can provide retinal cross-section
images at high resolution. OCT has allowed for longitudinal
evaluations of retinal degenerative disease processes, as well
as the impact of experimental therapies. Once the natural
history of RPE65 disease was established, these data served
as a control against which the degeneration of the treatment
group was compared. In addition, two other clever controls
were included: one using the untreated control eye and another using untreated retinal regions of the injected eye. The
results showed that ‘‘the great majority progressed along the
expected natural history, with rare regions showing no change
or greater than expected deviation’’ (p519). This finding
became even more striking in light of the fact that visual
improvement in these subjects was substantial (on average
1.6 log units) and persistent over time (up to 4.5 years).
To frame these sobering data, the authors reached back to
the animal model that originally put LCA2 gene therapy on
the map: the naturally occurring dog model of RPE65 disease. Natural history studies of the canine form of inherited
retinal dystrophy due to RPE65 were also done. A comparison of the degeneration of the ONL in dogs with that in
humans showed an interesting difference. In humans, dysfunction is always accompanied by degeneration; however,
RPE65 mutant dogs can have deteriorated vision early in the
disease in the absence of photoreceptor degeneration. Only
later in life, after about 5 years, ONL thinning becomes apparent and the disease course in dogs becomes similar to that
observed in humans. Importantly, gene therapy in the early
phase of the disease in dogs, prior to the onset of degeneration, was able to stem the degeneration of photoreceptor cells.
However, as with humans, treatment of dogs after degeneration had begun did not slow down photoreceptor loss.
The authors conclude that there appears to be a threshold
of accumulated changes as a result of the genetic lesion in
RPE65, after which photoreceptor death is inevitable, even
following reconstitution of the RPE65 in the therapeutic
target. These findings have implications for other inherited
forms of retinal degeneration and the design of gene therapy
interventions, as indeed in most preclinical studies for other
blindness genes, photoreceptor degeneration in animal
models can only be warded off when treated prior to the
onset of disease. The authors therefore call for a refinement
of the current therapeutic approach to enable a more complete therapeutic outcome. One suggested strategy is a
1
Department of Genetics and Department of Ophthalmology, Harvard Medical School, Harvard University, and Howard Hughes Medical
Institute Boston, MA 02114.
2
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Harvard
University, Boston, MA 02114.
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RETINAL GENE THERAPY COMING OF AGE
combined gene augmentation and neuroprotective therapy.
Of course, another obvious change would be treatment earlier in the disease course, prior to the point of no return.
While the models in the current study predict there is no
such therapeutic window in the human course of RPE65
disease, one test of this prediction is currently underway in
another RPE65 clinical study in which more subjects of
younger age were enrolled (Maguire et al., 2009). Future
studies are warranted to define such a window for other
forms of inherited retinal degeneration.
Where does this leave the field, and where do we go from
here? After the excitement of the results in these pioneering
studies, retinal gene therapy has gained momentum toward
the clinic. Do these data lessen the excitement and give cause
for a slowdown in translation in this arena? In what areas do
future therapies need to seek refinement in order to avert
these apparent unstoppable degenerative processes?
To address these questions, and to move forward from the
important issues raised by Cideciyan et al. (2008), it is critical
to better understand the nature of the death processes that
lead to the apparent point of no return highlighted in this
study. The degeneration in the retina of RPE65 patients may
be similar to that seen in other retinal diseases where there
is a non-autonomous cause of death. For example, in the
disease known as retinitis pigmentosa (RP), cone photoreceptors die, even though only rod photoreceptors express the disease gene. RP cones are fully functional until
the majority of rods die, at which point the cones become
dysfunctional and subsequently die (Hartong et al., 2006).
Similarly, studies of genetic mosaics in mice, in which wildtype rods were intermingled with mutant rods, showed that
wild-type rods died with kinetics similar to those of the
mutant rods (Huang et al., 1993; Kedzierski et al., 1998). There
have been various models made to explain why there is
nonautonomous death of photoreceptors including a toxin
released by dying rods, lack of a growth factor made by
healthy rods, oxidation, and metabolic problems with the
cones after the rods die (Punzo et al., 2012). However, there is
currently a lack of understanding of the disease processes.
Nonetheless, there is a possibility that one can provide a
nonspecific tonic for ailing photoreceptors, along the lines of
a growth factor or a metabolic booster. Indeed, delivery of a
growth factor to RP eyes is in a clinical trial, in which an
implanted device containing cells that secrete ciliary neurotrophic factor is being used. If successful, it is possible that a
growth factor and a prosurvival agent can be combined with
a specific gene therapy aimed at correcting the functional
deficit (Sieving et al., 2006).
While it is clear that the biology of degeneration in inherited retinal dystrophies uncouples from the primary genetic etiology at some point in the disease progression, we
argue that more sophisticated methods and approaches of
genetic therapeutic intervention may push back this point of
no return. Neither dogs nor humans treated following onset
of degeneration demonstrated a reduced rate of photoreceptor loss; however, we do know gene delivery in these
studies could be more efficient or be distributed more evenly
across the retina with novel technologies. In addition, expression of RPE65 was driven by a promoter with little or no
cell specificity, resulting in ectopic expression with possible
deleterious effects. Arguing against this possibility, however,
is the lack of degeneration observed in the dogs treated as
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puppies; although there may have been compensation by the
younger, less degenerated environment of the young dog. In
addition to effects of the transgene, the invasiveness of the
subretinal injection, as well as the limited area of the retina
that can be reached with this surgical route of administration, may be well tolerated in a nondegenerated retina, but
once degeneration has set in, it might be one insult too many.
Less invasive and more broadly distributed, yet equally efficient delivery, may overcome this. It is curious, however,
that there was not a more immediate increase in the degeneration rate if indeed the injection method was a contributing
factor. In short, technical advances may enable improvements on the current approach and allow for later intervention
that slows down retinal degeneration (Vandenberghe and
Auricchio, 2012).
Whether these data diminish the results that came out of
the initial RPE65 trials is left to the beholder; however, it
deserves to be restated that these pioneering studies met the
primary tenet in medicine—first, do no harm—and went
beyond by providing real-life clinical benefit in improvement
of vision. It would have been surprising if the first version of
a highly novel therapeutic paradigm was flawless and did
not require improvement. In fact, the excellent study at hand
demonstrates how essential human data are in the development of early stage therapeutic platforms because these
first clinical studies provide benchmarks and guideposts for
recalibration in case of failure and refinement in all other
cases. In our view, clinical translation should progress cautiously, without interruption, to help current generations of
patients. The data from human studies, improvement in the
therapeutic methods, and a deeper understanding of the
underlying disease processes, can each inform the other. This
will be an iterative process, hopefully with an increase in the
prolongation of vision at each step.
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CEPKO AND VANDENBERGHE
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Address correspondence to:
Dr. Luk H. Vandenberghe
Berman-Gund Laboratory for Retinal Degenerations
Howe Laboratory & Ocular Genomics Institute
Massachusetts Eye and Ear Infirmary &
Schepens Eye Research Institute
Harvard Medical School
20 Staniford Street
Boston, MA 02114
E-mail: [email protected]
Received for publication February 28, 2013;
accepted February 28, 2013.